Understanding seasonal telomere length dynamics in hibernating species.

Oxidative stress is thought to be one of the main causes of ageing as it progressively damages cell components throughout life, eventually causing cellular failure and apoptosis. In many organisms, telomeres shorten throughout life under the effect of, amongst other factors, oxidative stress, and are therefore commonly used as marker of biological ageing. However, hibernators, which are regularly exposed to acute oxidative stress when rewarming from torpor, are unexpectedly long-lived. In this review, we explore the causes of oxidative stress associated with hibernation and its impact on telomere dynamics in different taxa, focussing on hibernating rodents. We then speculate on the adaptive mechanisms of hibernators to compensate for the effects of oxidative stress, which may explain their increased longevity. Because winter hibernation appears to be associated with high oxidative stress, hibernators, particularly rodents, may periodically invest in repair mechanisms and antioxidant defences, resulting in seasonal variations in telomere lengths. This research shows how species with a slow life-history strategy deal with large changes in oxidative stress, unifying evolutionary and physiological theories of ageing. Because of the marked seasonal variation in telomere length, we also draw attention when using telomeres as markers for biological aging in seasonal heterotherms and possibly in other highly seasonal species.

Enhancing tumor endothelial permeability using MUC18-targeted gold nanorods and mild hyperthermia.

The Enhanced Permeability and Retention (EPR) effect, an elevated accumulation of drugs and nanoparticles in tumors versus in normal tissues, is a widely used concept in the field of cancer therapy. It assumes that the vasculature of solid tumors would possess abnormal, leaky endothelial cell barriers, allowing easy access of intravenous-delivered drugs and nanoparticles to tumor regions. However, the EPR effect is not always effective owing to the heterogeneity of tumor endothelium over time, location, and species. Herein, we introduce a unique nanoparticle-based approach, using MUC18-targeted gold nanorods coupled with mild hyperthermia, to specifically enhance tumor endothelial permeability. This improves the efficacy of traditional cancer therapy including photothermal therapy and anticancer drug delivery by increasing the transport of photo-absorbers and drugs across the tumor endothelium. Using single cell imaging tools and classic analytical approaches in molecular biology, we demonstrate that MUC18-targeted gold nanorods and mild hyperthermia enlarge the intercellular gaps of tumor endothelium by inducing circumferential actin remodeling, stress fiber formation, and cell contraction of adjacent endothelial cells. Considering MUC18 is overexpressed on a variety of tumor endothelium and cancer cells, this approach paves a new avenue to improve the efficacy of cancer therapy by actively enhancing the tumor endothelial permeability.

Genome Assembly of the Dyeing Poison Frog Provides Insights into the Dynamics of Transposable Element and Genome-Size Evolution.

Genome size varies greatly across the tree of life and transposable elements are an important contributor to this variation. Among vertebrates, amphibians display the greatest variation in genome size, making them ideal models to explore the causes and consequences of genome size variation. However, high-quality genome assemblies for amphibians have, until recently, been rare. Here, we generate a high-quality genome assembly for the dyeing poison frog, Dendrobates tinctorius. We compare this assembly to publicly available frog genomes and find evidence for both large-scale conserved synteny and widespread rearrangements between frog lineages. Comparing conserved orthologs annotated in these genomes revealed a strong correlation between genome size and gene size. To explore the cause of gene-size variation, we quantified the location of transposable elements relative to gene features and find that the accumulation of transposable elements in introns has played an important role in the evolution of gene size in D. tinctorius, while estimates of insertion times suggest that many insertion events are recent and species-specific. Finally, we carry out population-scale mobile-element sequencing and show that the diversity and abundance of transposable elements in poison frog genomes can complicate genotyping from repetitive element sequence anchors. Our results show that transposable elements have clearly played an important role in the evolution of large genome size in D. tinctorius. Future studies are needed to fully understand the dynamics of transposable element evolution and to optimize primer or bait design for cost-effective population-level genotyping in species with large, repetitive genomes.

Alpine salamanders at risk? The current status of an emerging fungal pathogen.

Amphibians globally suffer from emerging infectious diseases like chytridiomycosis caused by the continuously spreading chytrid fungi. One is Batrachochytrium salamandrivorans (Bsal) and its disease ‒ the 'salamander plague' ‒ which is lethal to several caudate taxa. Recently introduced into Western Europe, long distance dispersal of Bsal, likely through human mediation, has been reported. Herein we study if Alpine salamanders (Salamandra atra and S. lanzai) are yet affected by the salamander plague in the wild. Members of the genus Salamandra are highly susceptible to Bsal leading to the lethal disease. Moreover, ecological modelling has shown that the Alps and Dinarides, where Alpine salamanders occur, are generally suitable for Bsal. We analysed skin swabs of 818 individuals of Alpine salamanders and syntopic amphibians at 40 sites between 2017 to 2022. Further, we compiled those with published data from 319 individuals from 13 sites concluding that Bsal infections were not detected. Our results suggest that the salamander plague so far is absent from the geographic ranges of Alpine salamanders. That means that there is still a chance to timely implement surveillance strategies. Among others, we recommend prevention measures, citizen science approaches, and ex situ conservation breeding of endemic salamandrid lineages.

Evolutionary characteristics of the mitochondrial NADH dehydrogenase subunit 6 gene in some populations of four sympatric Mustela species (Mustelidae, Mammalia) from central Europe.

BACKGROUND: Selection on or reticulate evolution of mtDNA is documented in various mammalian taxa and could lead to misleading phylogenetic conclusions if not recognized. We sequenced the MT-ND6 gene of four sympatric Mustelid species of the genus Mustela from some central European populations. We hypothesised positive selection on MT-ND6, given its functional importance and the different body sizes and life histories of the species, even though climatic differences may be unimportant for adaptation in sympatry. METHODS AND RESULTS: MT-ND6 genes were sequenced in 187 sympatric specimens of weasels, Mustela nivalis, stoats, M. erminea, polecats, M. putorius, and steppe polecats, M. eversmannii, from eastern Austria and of fourteen allopatric polecats from eastern-central Germany. Median joining networks, neighbour joining and maximum likelihood analyses as well as Bayesian inference grouped all species according to earlier published phylogenetic models. However, polecats and steppe polecats, two very closely related species, shared the same two haplotypes. We found only negative selection within the Mustela sequences, including 131 downloaded ones covering thirteen species. Positive selection was observed on three MT-ND6 codons of other mustelid genera retrieved from GenBank. CONCLUSIONS: Negative selection for MT-ND6 within the genus Mustela suggests absence of both environmental and species-specific effects of cellular energy metabolism despite large species-specific differences in body size. The presently found shared polymorphism in European polecats and steppe polecats may result from ancestral polymorphism before speciation and historical or recent introgressive hybridization; it may indicate mtDNA capture of steppe polecats by M. putorius in Europe.

N-Cadherin Targeted Melanin Nanoparticles Reverse the Endothelial-Mesenchymal Transition in Vascular Endothelial Cells to Potentially Slow the Progression of Atherosclerosis and Cancer.

Endothelial-mesenchymal transition (EndoMT) of vascular endothelial cells has recently been considered as a key player in the early progression of a variety of vascular and nonvascular diseases, including atherosclerosis, cancer, and organ fibrosis. However, current strategies attempting to identify pharmacological inhibitors to block the regulatory pathways of EndoMT suffer from poor selectivity, unwanted side effects, and a heterogeneous response from endothelial cells with different origins. Furthermore, EndoMT inhibitors focus on preventing EndoMT, leaving the endothelial cells that have already undergone EndoMT unresolved. Here, we report the design of a simple but powerful nanoparticle system (i.e., N-cadherin targeted melanin nanoparticles) to convert cytokine-activated, mesenchymal-like endothelial cells back to their original endothelial phenotype. We term this process "Reversed EndoMT" (R-EndoMT). R-EndoMT allows the impaired endothelial barriers to recover their quiescence and intactness, with significantly reduced leukocyte and cancer cell adhesion and transmigration, which could potentially stop atheromatous plaque formation and cancer metastasis in the early stages. R-EndoMT is achieved on different endothelial cell types originating from arteries, veins, and capillaries, independent of activating cytokines. We reveal that N-cadherin targeted melanin nanoparticles reverse EndoMT by downregulating an N-cadherin dependent RhoA activation pathway. Overall, this approach offers a different prospect to treat multiple EndoMT-associated diseases by designing nanoparticles to reverse the phenotypical transition of endothelial cells.

Summer fades, deer change: Photoperiodic control of cellular seasonal acclimatization of skeletal muscle.

We found major seasonal changes of polyunsaturated fatty acids (PUFAs) in muscular phospholipids (PL) in a large non-hibernating mammal, the red deer (Cervus elaphus). Dietary supply of essential linoleic acid (LA) and α-linolenic acid (ALA) had no, or only weak influence, respectively. We further found correlations of PL PUFA concentrations with the activity of key metabolic enzymes, independent of higher winter expression. Activity of the sarcoplasmic reticulum (SR) Ca++-ATPase increased with SR PL concentrations of n-6 PUFA, and of cytochrome c oxidase and citrate synthase, indicators of ATP-production, with concentrations of eicosapentaenoic acid in mitochondrial PL. All detected cyclic molecular changes were controlled by photoperiod and are likely of general relevance for mammals living in seasonal environments, including humans. During winter, these changes at the molecular level presumably compensate for Arrhenius effects in the colder peripheral body parts and thus enable a thrifty life at lower body temperature.

Seasonal variation in telomerase activity and telomere dynamics in a hibernating rodent, the garden dormouse (Eliomys quercinus).

Telomere dynamics in hibernating species are known to reflect seasonal changes in somatic maintenance. Throughout hibernation, the periodic states of rewarming, known as inter-bout euthermia or arousals, are associated with high metabolic costs including shortening of telomeres. In the active season, if high energetic resources are available, telomere length can be restored in preparation for the upcoming winter. The mechanism for telomere elongation has not been clearly demonstrated, although the action of the ribonucleoprotein complex, telomerase, has been implicated in many species. Here we tested for levels of telomerase activity in the garden dormouse (Eliomys quercinus) at different seasonal time points throughout the year and across ages from liver tissues of male juveniles to adults. We found that telomerase is active at high levels across seasons (during torpor and inter-bout euthermia, plus in the active season) but that there was a substantial decrease in activity in the month prior to hibernation. Telomerase levels were consistent across age groups and were independent of feeding regime and time of birth (early or late born). The changes in activity levels that we detected were broadly associated with changes in telomere lengths measured in the same tissues. We hypothesise that i) telomerase is the mechanism used by garden dormice for maintenance of telomeres and that ii) activity is kept at high levels throughout the year until pre-hibernation when resources are diverted to increasing fat reserves for overwintering. We found no evidence for a decrease in telomerase activity with age or a final increase in telomere length which has been detected in other hibernating rodents.

The extinct Sicilian wolf shows a complex history of isolation and admixture with ancient dogs.

The Sicilian wolf remained isolated in Sicily from the end of the Pleistocene until its extermination in the 1930s-1960s. Given its long-term isolation on the island and distinctive morphology, the genetic origin of the Sicilian wolf remains debated. We sequenced four nuclear genomes and five mitogenomes from the seven existing museum specimens to investigate the Sicilian wolf ancestry, relationships with extant and extinct wolves and dogs, and diversity. Our results show that the Sicilian wolf is most closely related to the Italian wolf but carries ancestry from a lineage related to European Eneolithic and Bronze Age dogs. The average nucleotide diversity of the Sicilian wolf was half of the Italian wolf, with 37-50% of its genome contained in runs of homozygosity. Overall, we show that, by the time it went extinct, the Sicilian wolf had high inbreeding and low-genetic diversity, consistent with a population in an insular environment.

Protocol paper for SMART OPS: Shared decision-making Multidisciplinary Approach - a Randomised controlled Trial in the Older adult Population considering Surgery.

INTRODUCTION: The Australian population presenting with surgical pathology is becoming older, frailer and more comorbid. Shared decision-making is rapidly becoming the gold standard of care for patients considering high-risk surgery to ensure that appropriate, value-based healthcare decisions are made. Positive benefits around patient perception of decision-making in the immediacy of the decision are described in the literature. However, short-term and long-term holistic patient-centred outcomes and cost implications for the health service require further examination to better understand the full impact of shared decision-making in this population. METHODS: We propose a novel multidisciplinary shared decision-making model of care in the perioperative period for patients considering high-risk surgery in the fields of general, vascular and head and neck surgery. We assess it in a two arm prospective randomised controlled trial. Patients are randomised to either 'standard' perioperative care, or to a multidisciplinary (surgeon, anaesthetist and end-of-life care nurse practitioner or social worker) shared decision-making consultation. The primary outcome is decisional conflict prior to any surgical procedure occurring. Secondary outcomes include the patient's treatment choice, how decisional conflict changes longitudinally over the subsequent year, patient-centred outcomes including life impact and quality of life metrics, as well as morbidity and mortality. Additionally, we will report on healthcare resource use including subsequent admissions or representations to a healthcare facility up to 1 year. ETHICS AND DISSEMINATION: This study has been approved by the Hunter New England Human Research Ethics Committee (2019/ETH13349). Study findings will be presented at local and national conferences and within scientific research journals. TRIAL REGISTRATION NUMBER: ACTRN12619001543178.

Food availability positively affects the survival and somatic maintenance of hibernating garden dormice (Eliomys quercinus).

BACKGROUND: Torpor is an energy saving strategy achieved by substantial reductions of metabolic rate and body temperature that enables animals to survive periods of low resource availability. During hibernation (multiday torpor), the frequency of periodic rewarming-characterised by high levels of oxidative stress-is associated with shortening of telomeres, a marker of somatic maintenance. OBJECTIVES: In this study, we determined the impact of ambient temperature on feeding behaviour and telomere dynamics in hibernating garden dormice (Eliomys quercinus) over winter. This obligate hibernator prepares for hibernation by accumulating fat stores but can also feed during hibernation. METHODOLOGY: Food intake, torpor pattern, changes in telomere length, and body mass change were assessed in animals housed at experimentally controlled temperatures of either 14 °C (i.e., a mild winter) or 3 °C (i.e., a cold winter) over 6 months. RESULTS: When hibernating at 14 °C, dormice experienced 1.7-fold more frequent and 2.4-fold longer inter-bout euthermia, and spent significantly less time torpid, compared to animals hibernating at 3 °C. Higher food intake enabled individuals to compensate for increased energetic costs when hibernating at milder temperatures (14 °C vs. 3 °C), to buffer body mass loss and thus increase winter survival. Interestingly, we observed a significant increase of telomere length over the entire hibernation period, irrespective of temperature treatment. CONCLUSION: We conclude that higher temperatures during winter, if associated with sufficient food availability, can have a positive effect on the individual's energy balance and somatic maintenance. These results suggest that winter food availability might be a crucial determinant for the survival of the garden dormouse in the context of ever-increasing environmental temperatures.

Temporomandibular disorders-review of evidence-based management and a proposed multidisciplinary care pathway.

Temporomandibular disorders (TMDs) are a prevalent but complex group of conditions that cause orofacial pain. Temporomandibular disorders are recognized as one of the most common chronic pain conditions, alongside back pain and headache disorders. Given the competing theories surrounding what causes TMDs and limited high-equality evidence on optimally treating TMDs, clinicians often encounter challenges in developing an effective management plan for patients. Furthermore, patients will often seek advice from multiple health care providers from varying specialties, seeking curative management, often resulting in inappropriate treatments and no improvement in pain symptoms. Throughout this review, we explore the existing evidence base surrounding the pathophysiology, diagnosis, and management of TMDs. An existing United Kingdom-based multidisciplinary care pathway for the management of TMDs is described herein, highlighting the benefits of a multidisciplinary approach to patient care for TMDs.

Photothermal Attenuation of Cancer Cell Stemness, Chemoresistance, and Migration Using CD44-Targeted MoS2 Nanosheets.

Cancer stem-like cells (CSCs) play key roles in chemoresistance, tumor metastasis, and clinical relapse. However, current CSC inhibitors lack specificity, efficacy, and applicability to different cancers. Herein, we introduce a nanomaterial-based approach to photothermally induce the differentiation of CSCs, termed "photothermal differentiation", leading to the attenuation of cancer cell stemness, chemoresistance, and metastasis. MoS2 nanosheets and a moderate photothermal treatment were applied to target a CSC surface receptor (i.e., CD44) and modulate its downstream signaling pathway. This treatment forces the more stem-like cancer cells to lose the mesenchymal phenotype and adopt an epithelial, less stem-like state, which shows attenuated self-renewal capacity, more response to anticancer drugs, and less invasiveness. This approach could be applicable to various cancers due to the broad availability of the CD44 biomarker. The concept of using photothermal nanomaterials to regulate specific cellular activities driving the differentiation of CSCs offers a new avenue for treating refractory cancers.

Toxicity and assimilation of cellulosic copper nanoparticles require α-arrestins in S. cerevisiae.

The increased use of antimicrobial compounds such as copper into nanoparticles changes how living cells interact with these novel materials. The increased use of antimicrobial nanomaterials combats infectious disease and food spoilage. Fungal infections are particularly difficult to treat because of the few druggable targets, and Saccharomyces cerevisiae provides an insightful model organism to test these new materials. However, because of the novel characteristics of these materials, it is unclear how these materials interact with living cells and if resistance to copper-based nanomaterials could occur. Copper nanoparticles built on carboxymethylcellulose microfibril strands with copper (CMC-Cu) are a promising nanomaterial when imported into yeast cells and induce cell death. The α-arrestins are cargo adaptors that select which molecules are imported into eukaryotic cells. We screened α-arrestins mutants and identified Aly2, Rim8, and Rog3 α-arrestins, which are necessary for the internalization of CMC-Cu nanoparticles. Internal reactive oxygen species in these mutants were lower and corresponded to the increased viability in the presence of CMC-Cu. Using lattice light-sheet microscopy on live cells, we determined that CMC-Cu were imported into yeast within 30 min of exposure. Initially, the cytoplasmic pH decreased but returned to basal level 90 min later. However, there was heterogeneity in response to CMC-Cu exposure, which could be due to the heterogeneity of the particles or differences in the metabolic states within the population. When yeast were exposed to sublethal concentrations of CMC-Cu no resistance occurred. Internalization of CMC-Cu increases the potency of these antimicrobial nanomaterials and is likely key to preventing fungi from evolving resistance.

"Non-cytotoxic" doses of metal-organic framework nanoparticles increase endothelial permeability by inducing actin reorganization.

Cytotoxicity of nanoparticles is routinely characterized by biochemical assays such as cell viability and membrane integrity assays. However, these approaches overlook cellular biophysical properties including changes in the actin cytoskeleton, cell stiffness, and cell morphology, particularly when cells are exposed to "non-cytotoxic" doses of nanoparticles. Zeolitic imidazolate framework-8 nanoparticles (ZIF-8 NPs), a member of metal-organic framework family, has received increasing interest in various fields such as environmental and biomedical sciences. ZIF-8 NPs may enter the blood circulation system after unintended oral and inhalational exposure or intended intravenous injection for diagnostic and therapeutic applications, yet the effect of ZIF-8 NPs on vascular endothelial cells is not well understood. Here, the biophysical impact of "non-cytotoxic" dose ZIF-8 NPs on human aortic endothelial cells (HAECs) is investigated. We demonstrate that "non-cytotoxic" doses of ZIF-8 NPs, pre-defined by a series of biochemical assays, can increase the endothelial permeability of HAEC monolayers by causing cell junction disruption and intercellular gap formation, which can be attributed to actin reorganization within adjacent HAECs. Nanomechanical atomic force microscopy and super resolution fluorescence microscopy further confirm that "non-cytotoxic" doses of ZIF-8 NPs change the actin structure and cell morphology of HAECs at the single cell level. Finally, the underlying mechanism of actin reorganization induced by the "non-cytotoxic" dose ZIF-8 NPs is elucidated. Together, this study indicates that the "non-cytotoxic" doses of ZIF-8 NPs, intentionally or unintentionally introduced into blood circulation, may still pose a threat to human health, considering increased endothelial permeability is essential to the progression of a variety of diseases. From a broad view of cytotoxicity evaluation, it is important to consider the biophysical properties of cells, since they can serve as novel and more sensitive markers to assess nanomaterial's cytotoxicity.

Spectral characterization of cell surface motion for mechanistic investigations of cellular mechanobiology.

Understanding the specific mechanisms responsible for anabolic and catabolic responses to static or dynamic force are largely poorly understood. Because of this, most research groups studying mechanotransduction due to dynamic forces employ an empirical approach in deciding what frequencies to apply during experiments. While this has been shown to elucidate valuable information regarding how cells respond under controlled provocation, it is often difficult or impossible to determine a true optimal frequency for force application, as many intracellular complexes are involved in receiving, propagating, and responding to a given stimulus. Here we present a novel adaptation of an analytical technique from the fields of civil and mechanical engineering that may open the door to direct measurement of mechanobiological cellular frequencies which could be used to target specific cell signaling pathways leveraging synergy between outside-in and inside-out mechanotransduction approaches. This information could be useful in identifying how specific proteins are involved in the homeostatic balance, or disruption thereof, of cells and tissue, furthering the understanding of the pathogenesis and progression of many diseases across a wide variety of cell types, which may one day lead to the development of novel mechanobiological therapies for clinical use.

A Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of 3 Weeks of Orally Administered Gefapixant in Healthy Younger and Older Adults.

PURPOSE: Patients with chronic cough are typically female and have a mean age of ~ 60 years. However, initial pharmacokinetic (PK) characterization of the P2X3-receptor antagonist gefapixant, developed to treat refractory or unexplained chronic cough, was performed in healthy participants who were predominantly younger adult males. The objective of this Phase 1 study was to assess the safety, tolerability, and PK of gefapixant in younger (18-55 years) and older (65-80 years) males and females. METHODS: A randomized, double-blind, placebo-controlled study was conducted. Healthy adult participants were stratified into 4 cohorts by age and sex (younger males/females and older males/females) and randomized 4:1 (younger adults) or 3:1 (older adults) to receive gefapixant 300 mg twice daily (BID) for 1 week, followed by gefapixant 600 mg BID for 2 weeks or placebo. Safety, tolerability, and PK were assessed. RESULTS: Of 36 randomized and treated participants, 28 (100%) receiving gefapixant and 6 (75%) receiving placebo reported ≥ 1 adverse event (AE). The most common treatment-related AEs in the gefapixant group were taste related. Predefined renal/urologic AEs were reported by 7 (25%) participants receiving gefapixant (all mild to moderate in severity). Gefapixant exposure was generally lower in younger males compared with younger females and older adults; however, differences may have been due to estimated glomerular filtration rate. CONCLUSION: The safety profile of gefapixant 300-600 mg BID was generally consistent with previous studies. Additional characterization of gefapixant PK as a function of age and sex using population PK modeling is warranted.

REducing Colonoscopies in patients without significant bowEl DiseasE: the RECEDE Study - protocol for a prospective diagnostic accuracy study.

INTRODUCTION: Demand for colonoscopies and CT colonography (CTC) is exceeding capacity in National Health Service Trusts. In many patients colonoscopies and CTCs show no significant bowel disease (SBD). Faecal Immunochemical Testing (FIT) is being introduced to prioritise patients for colonoscopies but is insufficient to identify non-SBD patients meaning colonoscopy and CTC demand remains high. The REducing Colonoscopies in patients without significant bowEl DiseasE (RECEDE) study aims to test urine volatile organic compound (VOC) analysis alongside FIT to improve detection of SBD and to reduce the number of colonoscopies and CTCs. METHODS AND ANALYSIS: This is a multicentre, prospective diagnostic accuracy study evaluating whether stool FIT plus urine VOC compared with stool FIT alone improves detection of SBD in patients referred for colonoscopy or CTC due to persistent lower gastrointestinal symptoms. To ensure SBD is not missed, the dual test requires a high sensitivity, set at 97% with 95% CI width of 5%. Our assumption is that to achieve this sensitivity requires 200 participants with SBD. Further assuming 19% of all participants will have SBD and 55% of all participants will return both stool and urine samples we will recruit 1915 participants. The thresholds for FIT and VOC results diagnosing SBD have been pre-set. If either FIT or VOC exceeds the respective threshold, the participant will be classed as having suspected SBD. As an exploratory analysis we will be testing different thresholds. The reference comparator will be a complete colonoscopy or CTC. Secondary outcomes will look at optimising the FIT and VOC thresholds for SBD detection. An economic evaluation, using a denovo decision analytic model, will be carried out determine the costs, benefits and overall cost-effectiveness of FIT +VOC vs FIT followed by colonoscopy. ETHICS AND DISSEMINATION: Ethical approval was obtained by Liverpool Central Research Ethics Committee (20/NW/0346). TRIAL REGISTRATION NUMBER: RECEDE is registered on Clinicaltrials.gov NCT04516785 & ISRCTN14982373. This protocol was written and published before results of the trial were available.

How does early-life adversity shape telomere dynamics during adulthood? Problems and paradigms.

Although early-life adversity has been associated with negative consequences during adulthood, growing evidence shows that such adversity can also lead to subsequent stress resilience and positive fitness outcomes. Telomere dynamics are relevant in this context because of the link with developmental conditions and longevity. However, few studies have assessed whether the effects of early-life adversity on developmental telomere dynamics may relate to adult telomere dynamics. We propose that the potential links between early-life adversity and adult telomere dynamics could be driven by developmental constraints (the Constraint hypothesis), by the nature/severity of developmental adversity (the Resilience hypothesis), or by developmental-mediated changes in individual life-history strategies (the Pace of Life hypothesis). We discuss these non-mutually exclusive hypotheses, explore future research directions, and propose specific studies to test these hypotheses. Our article aims to expand our understanding of the evolutionary role of developmental conditions on adult telomere dynamics, stress resilience and ageing.

Reversing the Epithelial-Mesenchymal Transition in Metastatic Cancer Cells Using CD146-Targeted Black Phosphorus Nanosheets and a Mild Photothermal Treatment.

Cancer metastasis leads to most deaths in cancer patients, and the epithelial-mesenchymal transition (EMT) is the key mechanism that endows the cancer cells with strong migratory and invasive abilities. Here, we present a nanomaterial-based approach to reverse the EMT in cancer cells by targeting an EMT inducer, CD146, using engineered black phosphorus nanosheets (BPNSs) and a mild photothermal treatment. We demonstrate this approach can convert highly metastatic, mesenchymal-type breast cancer cells to an epithelial phenotype (i.e., reversing EMT), leading to a complete stoppage of cancer cell migration. By using advanced nanomechanical and super-resolution imaging, complemented by immunoblotting, we validate the phenotypic switch in the cancer cells, as evidenced by the altered actin organization and cell morphology, downregulation of mesenchymal protein markers, and upregulation of epithelial protein markers. We also elucidate the molecular mechanism behind the reversal of EMT. Our results reveal that CD146-targeted BPNSs and a mild photothermal treatment synergistically contribute to EMT reversal by downregulating membrane CD146 and perturbing its downstream EMT-related signaling pathways. Considering CD146 overexpression has been confirmed on the surface of a variety of metastatic, mesenchymal-like cancer cells, this approach could be applicable for treating various cancer metastasis via modulating the phenotype switch in cancer cells.